Process for controlling pathogens in container

ABSTRACT

A process for delivering a biocide to a container comprising admitting a biocide delivery device through an exit port of a urine container where the device is sized for passage through the exit port is disclosed.

This application is a division of U.S. Ser. No. 07/643,298 filed Jan.18, 1991 which is now U.S. Pat. No. 5,176,665.

FIELD OF INVENTION

This invention pertains to an antimicrobial device adapted for passagethrough the drainage port of a urinary drainage container. Thisinvention concerns also a patient-care system comprising, incombination, a urinary drainage container comprising a drainage port forinserting an antimicrobial device into the container, and anantimicrobial delivery device. The antimicrobial device delivers anagent into the container for preventing and eliminating unwantedpathogens inside the container. The invention relates also to a methodfor preventing and eliminating unwanted pathogens in a urine receivingcontainer by inserting through the drainage exit into the container, adevice for delivering an antimicrobial agent in the container.

BACKGROUND OF THE INVENTION

It is now generally acknowledged that indwelling catheterization inmedical, surgical, gynecological, and urological patients often leads toserious infections of the urogenital tract. Indwelling urethralcatheterization is performed in approximately 10 to 15 percent ofhospitalized patients. Despite the use of the most careful aseptictechnologies undertaken, while the catheter is in the patient,approximately fifty percent of the patients develop an infection, when acatheter is in place for twenty four hours or longer. Catheterization isharmful to the patient because (s)he is subjected to the risk ofcystitis, acute pyelonephritis and life-threatening septicemia, whichinfections carry a risk of mortality, as reported in Arch. InternalMed., Vol. 110, pp 703-11, (1962); Antimicrob. Agents Chemother., pp617-23, (1963); and Lancet, Vol. 1, pp 310-12 (1960).

The occurrence of the above-mentioned infections is encouraged by manycircumstances. These circumstances include prolonged use of indwellingFoley catheters often accompanied by the absence of a sterile insertionand maintenance technique, and by having the catheter connected to aclean, but not sterile drainage collection container placed in theimmediate vicinity of the patient's bed. These conditions and othercircumstances predispose a patient to infection as reported in UrinaryTract Infection and Its Management, edited by Kaye, D., Chapter 15,"care of the Indwelling Catheter," pp 256-66, (1972), published by theC. V. Mosby Company, St. Louis, Mo.,; and in "Factors Predisposing toBacteriuria During Indwelling Urethral Catheterization," New Eng. J.Med., Vol. 291, pp 215-23, (1974).

The prior art noted attempts have been made to reduce the incidence ofcatheter acquired infections and to reduce the presence of unwantedorganisms in drainage containers, but these attempts have not met withgeneral acceptance. For example, one attempt consists in systemicchemoprophylaxis achieved by orally administering an antibiotic such aschloramphenicol, penicillin or streptomycin. This attempt, however,affords no significant protection against the acquisition afterindwelling catheterization, as reported in Arch. Internal Med., Vol.110, pp 703-11, (1962); Acta Chiv. Scand., Vol. 118, pp 45-52 (1959);and Dis. Mon., pp 1-36, (Sept. 1960).

The medical and the patent literature are illustrative of attempts toeliminate the urinary drainage bag as a source of contamination leadingto urinary tract infection. These attempts for preventing orsubstantially eliminating unwanted organisms include adding a biocideduring manufacture to a drainage container, or placing a device insidethe container wherein the device releases a biocide. For example, liquidformalin is added to the urine collection container for controlling,that is, killing pathogens. This method, however, does not enjoy generaluse because there is a risk of siphoning formalin into the urinarytract, as reported in British Med. J., Vol. 2, pp 4233-25, (1964). InU.S. Pat. No. 4,233,263 the patentee Shaeffer disclosed adding 3%hydrogen peroxide solution to a urine bag for reducing the risk ofurinary tract infection. This method is inherently subjected to poorresults because of a lack of compliance. That is, each time urine isdeclined from the urinary drainage bag the hydrogen peroxide is drainedand the solution must be reintroduced into the urine bag. This procedurerequires mixing and agitation, and it is often accompanied by spillingof the solution. Also, hydrogen peroxide loses its strength over time.

The prior art, in U.S. Pat. Nos. 4,193,403 and 4,241,733 Langston et aldiscloses a device inside an urinary drainage bag. The device containsparaformaldehyde that depolymerizes to formaldehyde in the presence ofmoisture inside the urine drainage bag. While formaldehyde is anantimicrobial, it is not used because it may be injurious to an animalhost. In U.S. Pat. No. 3,312,221 patentee overment discloses an urinarydrainage bag having a porous plastic internal pouch containing anantimicrobial agent. The pouch is suspended so that incoming urinecascades over and through the pouch so that the antimicrobial agent willdissolve in the urine. However, an adequate dwell time of theantimicrobial agent in the urine is not assured by the quick flowprocess. Thus, the urine is undersatinated with antimicrobial agent witha high flow rate of urine into the urine container.

In view of the above presentation, it will be appreciated by thoseversed in the urinary drainage art, that a critical need exists for anovel and unique means for introducing an antimicrobial agent into anurinary container. The need exists for overcoming the difficultiesassociated with the prior art use of a preplaced delivery device insidethe container, that exhaust itself of antimicrobial agent and isnon-replaceable from outside with present, closed urinary drainagesystems. It will thus be appreciated that a pressing need exists for ameans that can be introduced into the container from outside thecontainer for providing an antimicrobial agent in the container.

OBJECTS OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide animprovement in urinary drainage collection, which improvement overcomesthe disadvantages associated with the prior art.

Another object of this invention is to provide a drainage collectionsystem comprising, in combination, a urine receiving containercomprising means for receiving through its exit port a device thatenters the container for delivering an antimicrobial agent forpreventing the proliferation of and/or the elimination of pathogens inthe container.

Another object of the invention is to provide an antimicrobial deliverydevice adopted for passage through the drainage port of a container fordelivering an antimicrobial agent in the container.

Another object of the invention is to provide an urinary drainagecontainer comprising a drainage container comprising a drainage portadapted for receiving a delivery device comprising dimensionscorresponding to the dimensions of the drainage port for facilitatingpassage of the device into the container.

Another object of this invention is to provide a delivery device that iseasily, inserted through the drainage port of a urine receivingcontainer for delivering an antimicrobial agent in the container, andwhich device embraces inventive simplicity, is inexpensive to make andis disposable.

Another object of the invention is to provide a delivery device for adrainage container, wherein the delivery device comprises a shape thatcorresponds to the internal shape of the drainage port of the container.

Another object of the invention is to provide a device for positioninginside a urinary drainage container through the drainage port of thecontainer, and which device can be inserted at the beginning of a urinedrainage program, or after the urine is drained from the container, oncea day, twice a day or more often over any number of days.

Another object of the invention is to provide a delivery device that cancomprise different antibacterial agents for killing bacteria in a urinereceiving container, and which device can embrace any geometric shapeadapted for pushing the device easily through the drainage port of thecontainer.

These and other objects of the present invention will become moreapparent upon a consideration of the drawings, the specification, andthe accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the drawing figures areas follows:

FIG. 1 is a fragmentary elevational view of a urine receptacle of thepresent invention comprising a drainage port adapted for inserting andantimicrobial agent dispensing device through the bottom of thereceptacle into the receptacle;

FIG. 2 is a fragmentary plain view, partly broken away for depicting theinside of a urine drainage container and for depicting a dispensingdevice entering the container through a bottom drainage port of thecontainer;

FIG. 3 illustrates a patient-care apparatus comprising a drainagecontainer and an antimicrobial agent dispensing device in the container,which device was inserted through a bottom drainage port into thecontainer;

FIG. 4 is a view of another embodiment of the invention illustrating areceptacle in opened section housing a dispensing device in urine,wherein the device was inserted through the exit drainage port of thereceptacle;

FIG. 5, 6, 7 and 8 depict, in opened view, delivery devices provided bythe invention for inserting through the exit port of a urine receivingcontainer into the container for delivering a biocide therein foreffecting a substantially germ-free environment inside the container;

FIG. 9 is a graph that illustrates bacterial growth of Escherichia coli,obtained from American Type Culture Collection (ATCC) 8739, in a urinecontainer, or bag, free of an antimicrobial agent;

FIG. 10 is a graph that illustrates a biocide concentration in a urinecontainer wherein a delivery device delivers an antimicrobial agent,bronopol. In FIG. 10, EVA denotes ethylene vinyl acetate copolymer and(40/60) denotes the device comprises 40 weight percent bronopol and 60weight percent ethylene vinyl acetate copolymer;

FIG. 11 depicts the results of a disinfectant delivery system, DDS,releasing the antimicrobial bronopol from ethylene vinyl acetatecopolymer, EVA, against Escherichia coli (ATCC 8739) in a urine bag over336 hours;

FIG. 12 depicts the results affected by a disinfectant delivery system,DDS, in a urine bag against the bacteria Pseudomonas aeruginosa (ATCC9027) over 336 hours;

FIG. 13 depicts the microbial growth of Pseudomonas aeruginosa (ATCC9027) in a urine bag that does not contain a disinfectant deliverysystem, DDS; and

FIG. 14 depicts a disinfectant released from two disinfectant deliverysystems in urine bags comprising artificial urine substantially free ofan added bacteria.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, wherein the drawings are examplesof various embodiments of the invention, and which examples are not tobe construed as limiting the invention, one embodiment of an urinarydrainage system is indicated in FIG. 1, by the numeral 10. In FIG. 1,urinary drainage system 10 comprises a container 11 comprising a frontwall 12, and a back wall, not seen in FIG. 1. The front and back wallsare made in one manufacture of a flexible, nontoxic plastic composition.The front wall and the back wall are joined around their peripheries 13to define an internal chamber for receiving a fluid. Container 11comprises a drainage port 14 for draining urine from the container.Drainage port 14 functions additionally as an entry passageway forpushing an antimicrobial dispensing device 15 into container 11. Theantimicrobial dispensing device 15 dispenses an antimicrobial agentinside container 11 for substantially eliminating the presence ofunwanted pathogens in container 11. Container 11 comprises a fluid entryport 16 designed for receiving an incoming tube for admitting fluid intocontainer 11. Entry port 16 is connected to a connector 17 attached tofront wall 12 of container 11. Container 11 optionally comprises a vent18 on front wall 12. Vent 18 comprises a bacterial filter for preventingcontamination from the atmosphere and for letting odors leave container11. In use, a drainage tube 19, also identified as a catheter lets urinedrain through the catheter from a patient into container 11, whereindispensing device 15 delivers an antimicrobial agent for killingunwanted pathogens present in container 11.

Drawing FIG. 2 discloses another embodiment provided by the invention.In drawing FIG. 2, there is seen a urinary receiving container 11comprising a front wall 12 and a back wall 20, seen at opened section21. Front wall 12 and back wall 20 define an internal chamber 22 forreceiving an incoming fluid. The front wall 12 and back wall 20 arejoined around their peripheries 13, and in another manufacture container11 can be extruded to define a container. In drawing FIG. 2, container11 comprises a fluid entry port 16 for receiving incoming catheter 19.Entry port 16 connects to connector 17 suitably attached to front wall12. Container 11 comprises a vent 18 comprising a bacterial filter tofilter bacteria passing from the atmosphere into chamber 22 of container11. Container 11 comprises a drainage port 14 for draining urine fromthe container and for pushing an antimicrobial dispensing device 15,seen in broken lines, in container 11.

Drawing FIG. 3 illustrates another embodiment of the inventioncomprising a patient care apparatus 10 manufactured with a volumetricscale 23 thereon for indicating the volume of fluid in container 11. Inthe embodiment depicted in FIG. 3, a dispensing device 15 is confinedwithin container 11 for controlling the presence of pathogens incontainer 11. Device 15 controls the multiplication and precludes thesurvival of pathogens, or unwanted infectious organisms in container 11by continually dispensing at a controlled rate an antibioticallyeffective amounts of an antimicrobial agent into container 11. Device 15by dispensing an antimicrobial agent for the aseptic management ofcontainer 11, concomitantly inhibits and prevents the migration ofinfectious organisms into catheter 19. This inventive embodimentsubstantially prevents the development of catheter induced infections ina patient that are introduced through an indwelling catheter; whichindwelling catheter passes through the urethra into the bladder, anddrains the bladder through the catheter tubing connected to fluiddrainage receptacle 11. In drawing FIG. 3, dispensing device 15 isintroduced through flexible outlet port 14 for draining container 11.Outlet port 14 is equipped with a pinch clamp 25 for draining fluid fromcontainer 11. In drawing FIG. 3, apparatus 10 is made with a handle 24for hanging container 11 from a stand placed in the vicinity of apatient's bed.

Drawing FIG. 4 depicts another patient-care apparatus 10 provided by theinvention. In drawing FIG. 4, patient-care apparatus comprises areceptacle 11 that is a container for receiving and storing a biologicalfluid 26. Receptacle 11 has both a volumetric scale 23 thereon forindicating the volume of fluid in receptacle 11, and a patientidentification area for indicating the origin of the biological fluid.Receptacle 11 of FIG. 4 is made with a front wall 12 with a sectionremoved for illustrating its back wall 21. Front wall 12 and back wall21 are made from a pair of thin, flat flexible plastic sheets such ispolyethylene, polypropylene, and the like. In one preferred manufacture,front wall 12 is made from a transparent plastic such is plasticizedpolyvinyl chloride, and rear wall 21 is made of an opaque plastic suchas polyvinyl chloride containing titanium dioxide. In this embodiment,the internal contents are visible as wall 12 and wall 21 arrangedback-to-back against each other highlight the internal contents ofreceptacle 11.

Receptacle 11 comprises an inlet means 16 for receiving an incomingcatheter that established fluid communication between the interior andthe exterior of receptacle 11. Receptacle 11 comprises an outlet port 14positioned at the bottom of receptacle 11 distant from inlet 16. Inantimicrobial dispensing device 15 is passed through inlet port 14 intocontainer 11 wherein the delivery device releases controlled and neededamounts of an antimicrobial agent into urine 26 for killing pathogens inurine 26. A hanging strap 24 is suitably attached to receptacle 11 forhanging receptacle 11 in a fluid receiving position at the bedside of acatheterized patient.

Delivery device 15 as used for the purpose of this invention dispensesan antimicrobial agent for producing an antiseptic environment. The termantimicrobial, as used herein, includes biocide, and means an agent thatdestroys, inhibits, and prevents the growth of pathogens, thepropagation, multiplication, and the like of unwanted organisms. Theterm organisms includes micro-organisms, bacteria, undulating bacteria,spirochetes, spores, spore-forming organisms, gram-negative organisms,gram-positive organisms, yeasts, fangs, molds, viruses, aerobes,anaerobes, mycobacteria, and the like.

Delivery device 15 comprises a body sized, shaped, and adapted forplacement through the exit port of a drainage container into thecontainer. Delivery device 15, in a preferred manufacture, comprises ashape and dimensions that correspond to the shape and dimensions of theexit port. Device 15 comprises at least one surface 28, or device 15comprises a multiplicity of surfaces 28, 29, for dispensing a biocidefrom device 15. Device 15 in another preferred embodiment comprises abiocide release rate wall 30, which wall surrounds at least in port, orsurrounds totally device 15. The release rate wall 30 meters a biocide,identified by dots 31, from device 15 at a controlled rate of time, overa prolonged period of time from 30 minutes to 336 hours. Device 15 canembrace any preselected geometric shapes, such as square, roundrectangle, triangle, crescent, and the like. Device 15 can bemanufactured as a rolled film, strip, rod, cylindrical rod, matrix,prism of various cross-sections, such as cruciform, hexagonal, and thelike. Device 15 can be seen in FIG. 5 manufactured as an extruded rodcomprising a biocide 31; device 15 can be manufactured as seen in FIG. 6by coextruding a release rate controlling wall 30 that surrounds aninternal composition 32 comprising a biocide 31; device 15 is seen inFIG. 7 in cross-section through the body of the device wherein device 15comprises a matrix 33 comprising a biocide 31; and device 15 is seen inFIG. 8 comprising a wall 30 with a sectioned removed which wall 30surrounds an internal comportment 34 comprising a biocide 31, whichbiocide is released over time for destroying or inhibiting the growth oforganisms in the urine drainage container.

DETAILED DISCLOSURE OF THE INVENTION

Dispensing device 15 used for the purpose of this invention comprises apolymeric composition, that houses an antimicrobial and permits therelease of the antimicrobial into a fluid environment of use. Thepolymeric composition is permeable to the passage of an antimicrobialand to the passage of fluid. The polymeric composition can be ahomopolymer, copolymer, terpolymer, non-cross-linked polymer,cross-linked polymer, diffusion polymer, microporous polymer, and thelike. Representative of polymers suitable for forming device 15 includeacrylic polymers and copolymers of methylmethacrylate; homopolymers andcopolymers of vinyl chloride including vinyl chloride-vinyl acetatecopolymer; chlorinated vinyl-chloride; polyethylene; ethylene-propylenecopolymer; chlorinated polyethylene; ethylene-vinyl acetate copolymer;styrene-butadiene copolymer; acrylonitrile-styrene-butadiene-terpolymer;polyvinylidene chloride; vinyl-chloride-acrylonitrile copolymer;vinylidene chloride-acrylate ester copolymer; polybutylene terphthalate;vinyl chloride-acrylate ester copolymer; cross-linked polyvinyl acetalssuch as cross-linked polyvinyl formal; cross-linked polyvinyl butyral;polyethers; sparingly cross-linked polyesters; polyurethanes;chlorosulfonated polyolefins; polyolefins; polyisoprene; polybutadiene;polysilicone; and the like. Exemplary of additional polymers forfabricating the device comprise ethylene-vinyl ester copolymers of thegeneral formula: ##STR1## wherein R is hydrogen, lower alkyl of 1 to 7carbons an aryl, and m is (4 to 80)% by weight and n is (4 to 80)% byweight and n is (100-m)% by weight. Typical alkyl groups include methyl,ethyl, propyl, isopropyl, tert-butyl, pentyl and hexyl. Typical arylgroups include phenyl. Representative ethylene-vinyl ester copolymers,named as the acetates, include ethylene-vinyl formate, ethylene-vinylacetate, ethylene-vinyl methylacetate, ethylene-vinyl ethylacetate,ethylene-vinyl propylacetate and the like. A preferred ethylene-vinylester copolymer includes ethylene-vinyl acetate having a vinyl acetatecontent of about 4 to 80% by weight of the total, a melt index of about0.1 to 1000 grams per ten minutes, a density of 0.920 to 1.09, and afrequency of acetoxy groups on the polyethylene backbone of 1/150 to1/35. Ethylene-vinyl ester copolymers are commercially available andthey are described in U.S. Pat. Nos. 2,200,429; 2,396,785 and 2,947,735;and British Pat. Nos. 569,927 and 582,093; and in Crystalline OlefinPolymers, edited by Raff, R. A. V. and Doak, D. W., Part II, pages 261to 266, 1964, published by Interscience Publishers, New York. Exemplaryof a segmented thermoplastic copolyester elastomer consistingessentially of a multiplicity of recurring long chain ester units andshort chain ester units joined head-to-tail through ester linkages, thelong chain ester units being of the formula: ##STR2## and the shortchain ester units being of the formula: ##STR3## where G is a divalentradical remaining after the removal of terminal hydroxyl groups from apoly(alkylene oxide) glycol having a molecular weight of about 400 to4000 and a carbon-to-oxygen ratio of about 2.0 to 4.3, R is a divalentradical remaining after removal of carboxyl groups from a dicarboxylicacid having a molecular weight less than about 300, and D is a divalentradical remaining after removal of hydroxyl groups from a diol having amolecular weight less than about 250, provided the short chain esterunits constitute about 30% to about 90% by weight of the copolyester, atleast about 70% of the radicals represented by D are 1,4-butyleneradicals and at least about 70% of the radicals represented by R are1,4-phenylene radicals, with the sum of the percentages of R radicalswhich are not 1,4-phenylene radicals and of the D radicals which are not1,4-butylene radicals not exceeding about 30. The polymers embraced byformula (1) and (2) are commercially available under the trademarkHytrel® polymer. These polymers and methods for preparing them aredescribed in U.S. Pat. Nos. 3,651,014; 3,763,109, and 3,766,146. Thedisclosure of these patents with respect to the manufacture,composition, and properties of the polymers is incorporated herein byreference. The preferred copolyesters of formula (1) and (2) for use inthe invention are those wherein the short chain ester units constituteabout 30% to about 60% by weight of the copolyester, G in formula (1) isa poly(alkyleneoxy) radical wherein the alkylene group is of 2 to 4carbon atoms, all of the D radicals of formula (2) are 1,4-phenylene. Ofthese preferred copolyesters those wherein G in formula (1) is apoly(tetramethyleneoxy) radical having a molecular weight of 800 to 1200are particularly preferred for the present purpose. The polymers usedherein are disclosed in Handbook of Common Polymers, by Scott et al,1971, published by CRC Press, Cleveland, Ohio; in Modern PlasticsEncyclopedia, 1979, published by McGraw-Hill Inc., New York, N.Y.; andin Handbook of Plastics and Elastomers, by Harper, 1976, published byMcGraw-Hill Inc., San Francisco, Calif.

The antimicrobial agent useful for the purpose of the invention includea member selected from the group consisting essentially of a phenol,quaternary ammonium biocides, surfactant biocides, chlorine-containingbiocides, quinoline, quinaldinium, lactone, antibiotics, dye,thiosemicarbazone, quinone, sulfa, carbamates, urea, salicylamide,carbanilide, amide, guanide, amidine, imidazoline antimicrobial agents.

Exemplary antimicrobial dyes include acridine, acriflavine, aminacrinehydrochloride, proflavin hemisulfate, triphenylmethane, magenta, crystalviolet, scarlet red, pararosaniline, and rosaniline. Exemplary chlorinereleasing biocides include sodium hypochlorite, oxychlorosene,chloramine, dichlorodimethylhydantoin, halazone, dichloramine,chlorasine, succinchlorimide, trichloroisocyanuric acid,dichloroisocyanurate, trichloromelamine, dichloroglycoluril, halogenateddialkyl-hydantoin, and halane.

Exemplary antimicrobial quinaldinium and quinoline biocides aredequalinium, laurolinium, hydroxyquinoline, lioquinol, chlorquinaldoland halquinol. Exemplary quaternary ammonium biocides include pyridiniumbiocides, benzalkonium chloride, cetrimide, benzethonium chloride,cetylpyridinium chloride, chlorphenoctium chloride, cetylpyridiniumchloride, chlorphenoctium amsonate, dequalinium acetate, dequaliniumchloride, domiphen bromide, laurolinium acetate, methylbenzethoniumchloride, myristyl-gamma-picolinium chloride, ortaphonium chloride, andtriclobisonium chloride. Exemplary furans include griseofulvin,nitrofurfural, nitrofurazone, nitrofurantoin, furazolidone, andfuraltadone.

Exemplary phenol antimicrobial include a member selected from the groupconsisting essentially of chlorinated phenol, cresol phenol, thymol,chlorocresol, chloroxylenol, hexachlorophane, bisphenols,amylmetacresol, bithionol, chlorothymol, dichloroxylenol chiorophene,p-chlorophenol, p-phenylphenol, trinitrophenol, dichlorobisphenol, andbromochlorobisphenol. Exemplary antibiotics include penicillins,gentemyctin, aminoglycosides, benzylpenicillin, ampicillin,tetracyclines, cephalosporins, neomycin, chloramphenicol, vancomycin,fudicin, rifampicin, cephaloridine, erythromycin, actinomycin, neomycin,polymyxin, colistin, gentamicin, bactriun, carbenicillin andstreptomycin, Exemplary lactones include propiolactone. Exemplary ureabiocides include noxytiolin, polynoxylen and triclocarbon.

Examples of other antimicrobial useful for the purpose of the inventionare chlorhexidine gluconate, chlorhexidine, chlorhexidine acetate,chlorhexidine hydrochloride, dibromopropamide, halogenateddiphenylalkanes, cibromsalan, metabromsalan, tribromsalan, carbanilide,salicylanilide, tetrachlorosalicylanilide, trichlorocarbanilide,propamide isethionate, pentamidine, picloxydine, mendalamine,methenamine salts, the acid addition and quaternary, methenaminemandelate, bronopol polyoxmethylene esters such as polyoxmethylenediester, polyoxmethylene diacitate, and the like, and mixtures thereof.

The amount of antimicrobial agent in device 15 generally will be about0.1% to 80% by weight, with a more preferred amount of 5% to 50% byweight. The device can be manufactured for releasing anti-invectiveamounts of antimicrobial agent over a prolonged period from severalhours to 30 days or longer, with a more preferred period of 30 minutesto 336 hours. Delivery systems that release a biocide for 30 minutes to720 hours also are provided by the invention for prolonged biocidialactivity. The devices of the invention release from 10 mg to 750 mg perhour, or higher. One device can be used at a time, or two or moredevices can be used at a time. The devices can be used in succession,and more than one device can be used simultaneously.

The antimicrobial agent kills, prevents or retards the presence ofharmful or unwanted micro-organisms inside a urine container. Typicalmicro-organisms include the fungi Aspergillus niger, Aspergillus flavus,Rhizopus nigricans, Cladosporium herbarium, Epidermophyton floccosum,Trichophyton mentagrophytes, Histoplasma capsulatum, and the like. Theterm, "micro-organisms," also includes Pseudomonas aeruginosa,Escherichia coli, Proteus vulgaris, Staphyloccus aureus Streptococcusfaecalis, Klebsiella, Enterobacter aerogenes, Proteus mirabills, othergram-negative bacteria and other gram-positive bacteria, mycobactin, andthe like. The term also embraces yeast such as Saccharomyces cerevisiae,Canndida albicans, and the like. Additionally, spores ofmicro-organisms, viruses and the like, are within the intent of theinvention.

The biocides are disclosed in Disinfection, Sterilization andPreservation, by Block, (1977), published by Lea & Febiger,Philadelphia, Pa.; in Inhibition and Destruction of Microbial Cells, byHugo, (1971), published by Academic Press, New York, N.Y.; inMartindale, The Extra Pharmacopoeia, edited by Blacow, published by TheLondon Pharmaceutical Press, London; and in U.S. Pat. No. 4,445,889.

Those skilled in the art to which this invention pertains can select apolymer for forming a device, and for selecting a wall-forming polymerby measuring the rate of diffusion through a polymeric material. Varioustechniques can be used to determine the permeability of a homopolymer,copolymer or terpolymer to the passage of a biocide. One method that canbe used is to position a film of the polymer, of known thickness, as abarrier between a rapidly stirred, saturated solution of the biocide anda rapidly stirred solvent bath, at a constant temperature, typically 25°C., and periodically measuring the concentration in the biocide solutionand in the solvent bath. Then, by plotting the biocide concentration inthe solvent bath versus time, the absence of the degree of permeability,P, of the polymeric film is determined by Fick's Law of Diffusion.Fick's Law of Diffusion is expressed by the following equation (1):

    Slope of plot=(Q.sub.1 -Q.sub.2 /t.sub.1 -t.sub.2)=PAc/h

wherein

Q₁ =cumulative amount of drug in solvent in micrograms at t₁.

Q₂ =cumulative amount of drug in solvent in micrograms at t₂.

t₁ =elapsed time to first sample, i.e., Q1

t₂ =elapsed time to second sample, i.e., Q2

A=area of film in cm

By determining the slope of the plot, i.e., [Q₁ -Q₂ /t₁ -t₂ ] andsolving the equation using the known or measured values of A, C and h,the permeability P constant in cm² /time of the film for a given biocideis readily determined. The procedures used to determined the rate ofrelease through the polymer can be ascertained easily by standardtechniques known to the art as recorded in J. Pharm. Sci., Vol. 52, pp1145-49, (1963); ibid, Vol. 53, pp 798-802 (1964); ibid, Vol. 54, pp1459-64, (1965); ibid, Vol. 55, pp 840-43 and 1224-39, (1966); Encyl.Polymer Sci. Technol., Vol. 5 and 9, pp 65-82 and 794-807, (1986); thereferences cited therein, and the like.

The dispensing device of the invention in one embodiment, can be made byblending a polymer and an antimicrobial agent to yield a homogenouscomposition. The composition can be melt extruded into an preselectedshape, such as fiber, rod, and the like. The composition, in anotherembodiment can be co-extruded with an outer wall forming polymer toprovide an antimicrobial release rate wall that surrounds an internalmatrix comprising the active antimicrobial agent. The polymericcomposition is extruded by a forced flow through a forming die, whichdie is shaped to produce the required cross-section. Inherent in theextrusion process is the softening, by heat, or optionally, by solvent,of the composition being formed so that it can be conveyed and formedinto the desirable final shape. The process takes place with anextruder, a processing machine convention to the plastic industry. Theextruder that can be used for the present purpose include a positivedisplacement, a raw extruder, continuous-flow ram extruder, gear-pumpextruder, intermeshing-twin screw extruder, viscous-drug extruder,single stage extruder, screwless extruders, and the like can be extrudedinto a preselected shape, such as fiber, rod, egg, star, and the likeshapes. The composition, in another embodiment, can be co-extruded withan outer wall-forming polymer to provide a release rate wall thatsurrounds an internal matrix comprising the active antimicrobial agent.The polymeric composition is extruded by a forced flow of thecomposition through a shape-forming die, which die is shaped to producethe required cross-section. The extrusion process operates by softeningthe composition, by heat, or optionally by solvent, so the extrudablecomposition formed can be conveyed and formed into the desired finalshape. The process takes place with an extruder, which is a processingmachine known to the plastic industry. Representative of extruders thatcan be used for the present purpose include a positive displacementextruder, a ram extruder, continuous-flow ram extruder, gear-pumpextruder, intermeshing-twin screw extruder, viscous-drug extruder,single stage extruder, screwless extruder, and the like. Procedures foroperating extruders and extruders are known in the Encyclopedia ofPolymer Science and Technology, Vol. 8, pp 533 to 587, (1968) publishedby John Wiley & Sons, New York, N.Y.

DETAILED DISCLOSURE OF EXAMPLES

The following examples well serve to further illustrate the presentinvention, but the invention is not intended to be limited thereto.

EXAMPLE 1

A dispensing device comprising a rod shape is prepared by blending theantimicrobial agent bronopol with ethylene-vinyl acetate copolymercomprising a vinyl acetate content of 33%, in a high intensity mixer toproduce a homogenous blend. The ratio of the antimicrobial agent to thecopolymer is 70% bronopol based on 100% weight basis. The compositioncomprising the antimicrobial and the copolymer were melt extruded toform a dispensing device comprising a rod shape. The rod shapecorresponds to shape of the exit port of an urinary drainage container,wherein when the rod is pushed therethrough it dispenser theantimicrobial bronopol for killing the pathogens in the container.

EXAMPLE 2

The above procedure is followed in this example, with the addedmanufacturing procedure that the rod is surrounded with a wall byco-extruding the composition with an outer wall-forming compositioncomprising the polymer Hytrel® to yield a wall 5 mil thick. Thedispensing device provided by Examples 1 and 2 dispense 25 to 50 μg/mlof antimicrobial bronopol for killing pathogens in a 2000 ml/day urineoutput into a urine drainage container. The invention providesdispensing device that dispenses from 20 to 80 μg/cm² hr for controllingpathogens in a urine container receiving 83 ml/hr of urine. Theantimicrobial bronopol is chemically known as2-bromo-2-nitro-1,3-propanediol. The Hytrel® polymer forming the releaserate wall is a block copolymer comprising 33% tetramethyleneterephthalate and 67% poly(tetramethyl ether) glycol terephthalate. Thedispensing device comprising an outer wall surrounding the inner matrixrod exhibited a combined outside diameter of 0.558 cm and a length of11.1 cm for a total area of 20 cm². The initial release of bronopol is245 μg/cm² hr with a steady state release of bronopol of 56 μg/cm² hr.Two such dispensing devices (40 cm²) will provide a biocidal unit amountof bronopol to kill pathogens.

EXAMPLE 3

Following the above Examples, a dispensing device is manufactured with a0.559 cm diameter as a heat extruded tube having a 0.2 cm bore and awall thickness of 0.18 cm. The tube is sleeved with a releasecontrolling wall comprising a polymer selected from the group consistingof ethylene-vinyl acetate copolymer, and tetramethylene terephthalatepoly(tetramethyl ether) glycol terephthalate copolymer. AccompanyingFIG. 8 depicts the release rate for one dispensing device provided bythe invention.

EXAMPLE 4

A dispensing device of tubular shape is made as follows: first 45 gramsof powdered aminacrine hydrochloride is blended for 10 to 15 minutes at25° C. on a two-roll mill, with 55 grams of powdered, transparentethylene-vinyl acetate copolymer having a vinyl acetate content of 28%weight, to produce a film consisting of a homogenous dispersion of theantimicrobial agent in the copolymer. Next, the film is ground in arotary grinder to produce particles sized 1/16 to 1/2 inches, averagesize, and the particles then transferred to the hopper of an extruder.The particles were extruded through a tubing die at 60° to 70° C. toyield a dispensing device. The device had an outside diameter of 5 mm,an inside diameter of 2.2 mm and a length of 5 cm. THe dispensing deviceexhibits a steady-state delivery of an effective amount of antimicrobialover a prolonged period of 24 hours. The device is non-erodible andkeeps its integrity during its residency in a urine environment of use.

EXAMPLE 5

A dispensing device for delivering methenamine hydrochloride, anantimicrobial agent, is prepared as follows: first 50 grams of theantimicrobial agent are ground to a powdered state and fed to a tworoller mill for blending with an olefin polymer comprisingethylene-vinyl acetate copolymer having a vinyl acetate content of 18%to produce a composition in film shape. The film composition comprisingthe olefin polymer and the antimicrobial agent is removed from the mill,cut into sections and fed to a coextruder. The coextruder was previouslycharged with a wall forming butyleneterephthalate)-poly-(tetrahydrofuran) copolymer, and the olefinantimicrobial composition as a rod surrounded by the wall formingpolymer. The device keeps it integrity in the presence of urine andreleases the antimicrobial agent at a controlled rate over a prolongedperiod of 35 hours.

EXAMPLE 6

The release rate of a dispensing device is measured in a syntheticurine. The synthetic urine is prepared in two separate solutions. Onesolution comprises dextrose (C₆ H₁₂ O₆), having a concentration of 0.83g/l, magnesium sulfate (MgSO₄.H₂ O), having a concentration of 1.54 g/land urea [(NH₂)₂ CO] having a concentration of 18.0 g/l. The secondsolution comprises dipotassium monohydrogen phosphate, K₂ HPO₄, having aconcentration of 4 g/l, disodium monohydrogen phosphate, Na₂ HPO₄.H₂ O,having a concentration of 2.68 g/l, monosodium dihydrogen phosphate,NaH₂ PO₄.H₂ O, having a concentration of 1.62 g/l, sodium citrate, C₆ H₅NaO₇. 2H₂ O, having a concentration of 1 g/l, sodium chloride, NaCl,having a concentration of 5.3 g/l, and ammonium sulfate, (NH₄)₂ SO₄,having a concentration of 1.2 g/l. The first solution is filteredthrough a 0.2 μm filter. The second solution is autoclaved for 17minutes at 121° C. and 15 psi pressure. The two solutions are combinedafter the second solution is cooled to room temperature.

The synthetic urine is pumped into a series of urine drainagecontainers. The containers were charged at a rate of 75 ml/hr. All thecontainers received an initial inoculation of Escherichia coli atapproximately 10⁴ cells per container. Samples were removed at variousperiods for analysis. The containers were emptied every 24 hours justprior to reinoculation. A dispensing device comprising ethylene-vinylacetate copolymer and bronopol and shaped like a flexible rod isinserted through the exit port of a urine drainage container.Accompanying FIG. 9 depicts the microbial growth of Escherichia coli ina urine container comprising synthetic urine and free of a deliverydevice. Accompanying FIG. 10 depicts the concentration of theantimicrobial bronopol, at the end of every 24 hours, in a urinedrainage container comprising synthetic urine, free of bacteria, andwherein the delivery device consists of ethylene-vinyl acetate copolymer(EVA) comprising bronopol, 40% bronopol-60% copolymer (40/60), whichdevice was inserted through the exit port of the drainage container. Theurine container was emptied every 24 hours prior to being infused withsynthetic urine. Accompanying FIG. 11 depicts the concentration ofEscherichia coli in a urine drainage container containing syntheticurine, and wherein the container comprises a delivery device (DDS)containing bronopol in a matrix comprising ethylene-vinyl acetatecopolymer, (EVA 210) wherein the device comprises 40% bronopol to 60%copolymer (40/60).

EXAMPLE 7

The operability and efficiency of an urinary bag disinfectant deliverysystem (DDS) was demonstrated as follows: first, synthetic urine wasinfused into urinary bags at a rate of 75 ml/hr. The bags received aninitial inoculation of approximately 10₄ microorganisms per bagdelivered through the exit port into the urinary bags. The bags weredrained and reinoculated daily with 10³ -10⁴ microorganisms per bag fortwo weeks. The DDS was inserted through the exit port into the urinebags, wherein the DDS maintained the synthetic urine sterile for theduration of the test period. In the control bags, bags without DDS, themicroorganisms count increased 10⁷ -10⁹ CFU, colony forming unit, permilliliter after the first 2 to 3 days and maintained that level for theremainder of the test period. Accompanying FIGS. 12 and 13,respectively, depict examples of treated and untreated urinary bagsinoculated with microorganisms. Accompanying FIG. 14 depictsconcentration-time profiles in urine bag 1 and urine bag 2, for thedisinfectant bronopol in synthetic urine, over a period of more than onemonth. The steady state disinfectant release rate was determined to bethe equivalent to the minimum bactericidal concentration (MBC) of thepathogens evaluated in the study. The DDS used in the studiesaccompanying FIGS. 12, 13 and 14, comprised a ethylene-vinyl acetatecopolymer matrix comprising bronopol with the matrix was surrounded witha wall comprising poly(butylene terephthalate)poly(tetrahydrofuran)block copolymer.

EXAMPLE 8

The above examples are repeated in this example wherein the deliverysystem is sized, shaped and adopted for pushing through the exit port ofa urine bag. The device in the example comprises a matrix ofpolysilicone surrounded with a release rate wall comprisingethylene-vinyl acetate copolymer. The biocide in the matrix comprisesthe anti-infective biocide chlorhexidine, methenamine iodobenzylate,methenamine camphorate, methenamine allyl iodide, methenamine hippurate,methenamine hydriodide, or methenamine tetraiodide.

The biocide is dispensed by the device to kill, cleanse, prevent and/orretard the presence or propagation of harmful or unwantedmicro-organisms as defined supra. The micro-organisms include the fungiAspergillus niger, Aspergillus flavus, Rhizopus nigricans, Cladosporiumherbarium, Epidermophyton floccosum, Trichophyton mentagrophytes,Histoplasma capsulatum, and the like the term micro-organisms alsoincludes antibacterial activity against Pseudomonas aeruginosa,Escherichia coli, Proteus vulgaris, Staphyloccus aureus Streptococcusfaecalis, Klebsiella species, Enterobacter aerogenes, Proteus mirabills,other gram-negative bacteria and other gram-positive bacteria,mycobactin and the like. The term also embraces yeast such asSaccharomyces cerevisiae, Canndida albicans, and the like. Additionally,spores of micro-organisms, viruses and the like, are within the intentof the invention.

METHOD OF PRACTICING THE INVENTION

The invention concerns also an improvement in a method of using theinvention, wherein the method comprises (a) introducing an indwellingcatheter into a patient in need of catheterization; (b) connecting thecatheter to a urine receiving container; (c) admitting into the urinecontainer through its exit port a device for releasing an antimicrobialagent into fluid present in the container, which agent substantiallyinhibits the growth of infectious organisms in the fluid, and whereinthe improvement in the device comprises: (1) a body sized and shaped forpassage through the exit to 30 days in the fluid, said body comprising apolymeric composition an agent into the fluid; (2) an antimicrobialagent in the body in an effective amount for substantially preventingfor substantially preventing the growth of organisms in the fluidcontainer; and, (4) releasing the agent from the surface of the device,with the device continually dispensing the antimicrobial agent or acontrolled rate in an antimicrobially effective amount into thecontainer for inhibiting the growth of infectious organisms in thecontainer, and concomitantly inhibiting the introduction of infectiousorganisms into the indwelling catheter, thereby preventing thedevelopment of a catheter induced infection in the patient.

It will be understood by those versed in the medico-surgical andpatient-care arts, that in the light of the present specification,drawings and the accompanying claims, this invention makes available tothe art both a novel and useful combination patient care and adispensing device endowed with beneficial properties. And, while theinvention can be used for collecting all kinds of biological fluids, itwill be further understood by those versed in the art that manyembodiments of this invention can be made without departing from thescope of the invention. Accordingly, it is to be understood theinvention is not to be construed as limited, but it embraces allequivalents inherent herein.

We claim:
 1. A method for placing a delivery device comprising anantimicrobial agent into a urine receiving container, said containercomprising a wall that surrounds a urine receiving space, an entry portthat lets urine into the container, and an exit port distant from theentry port for draining the container; and, wherein said methodcomprises admitting the delivery device through the exit port into thespace for placing the delivery device in the container.